Medicament with an anti-inflammatory and anti-ulcerous action

ABSTRACT

For anti-ulcerous and anti-inflammatory treatment, a medicament is administered to a patient consisting of N-(2-phenyl-2isoamyloxy)-ethyl-pyrrolidine. The medicament can be administered parenterally in an amount of 10 to 50 mg/day or orally in an amount of 100 to 220 mg/day or rectally in an amount of 150 to 300 mg/day.

United States Patent [1 1 Mauvernay et al.

[451 Apr. 17,1973

MEDICAMENT WITH AN ANTI- INFLAMMATORY AND ANTI- ULCEROUS ACTIONInventors: Roland Yves Mauvemay, Riom; Norbert Busch, Loubeyrat, both ofFrance Assignee: Societe Anonyme dite: Centre Europeen de RecherchesMauvemay- Cerm, Riom, France Filed: Dec. 21, 1971 Appl. No.: 210,586

us. Cl. .424/274 Int. Cl. ..A6lk 27/00 Field of Search ..424/274 [56]References Cited OTHER PUBLICATIONS Chem. Abst. Vol. 72 (1970) 2l607e.

Primary ExaminerStanley J. Friedman Attorney-Eric H. Waters et a1.

[ ABSTRACT For anti-ulcerous and anti-inflammatory treatment, a

4 Claims, No Drawings This compound is a known solid crystalline productwhich has been described as having pharmacologically useful properties,namely spasmolytic, vagolytic, anticholinergic and anti-depressiveactivities.

The present invention resides in the discovery that in certain forms andin certain doses this compound also possesses anti-ulcerous andanti-inflammatory properties which have not been described heretofore.

The compound may be prepared from styrene by a two-stage method which isdescribed below by way of example.

a. Preparation of (2-phenyl, 2-isoamyloxy) ethyl bromide 1.6 M ofterbutyl hypobromide are added dropwise with stirring to a mixture of130 g styrene and 300 ml isoamyl alcohol while maintaining thetemperature of the reaction mixture at about-C.

The reaction product is concentrated under vacuum (about mm Hg) on awater-bath at a temperature of about 45C. The residue is washed severaltimes in water, dried over anhydrous sodium sulphate and finallydistilled under vacuum to obtain a colorless liquid. (E 98-99C; n1.5130).

In this way there is obtained 135-140 g (2-phenyl, 2-

isoamyloxy)ethyl bromide.

b. Preparation of final product in the form of its hydrochloride Thefollowing mixture is refluxed with stirring for 10 hours 1 17 g of(2-phenyl, 2-isoamyloxy) ethyl bromide 61,5 g of pyrrolidine 250 mltoluene The pyrrolidine hydrobromide formed is filtered off and thetoluene then removed under vacuum. The residue is then taken up in 4NHCL. The resultant aqueous solution is washed with ether and madealkaline by the addition of a 50 percent solution of NaOH. The alkalinesolution is extracted with ether and the ethereal phase dried overanhydrous sodium sulphate after which it is distilled under vacuum,after removing the solvent, to give 90g of a colorless oil having anamine odor.

(E 121C; n 1.4978).

The hydrochloride is prepared in a conventional manner by dissolving theamine in anhydrous ether and adding the necessary amount of gaseous, dryhydrogen chloride dissolved in absolute alcohol.

The resultant product is a white crystalline powder melting at 150C,which is very soluble in water and alcoho], and virtually insoluble inether and ethyl acetate. The product has the following analysis NCalculated 4.70% Cl Calculated 1 1.90%

N Found 4.65% Cl Found l 1.90%

The anti-inflammatory and anti-ulcerous activities of this compound havebeen demonstrated by the following pharmacological tests.

- l Anti-inflammatory action This was demo nstra ted by the followingstudies 1. In vitro (inhibition of the action of biological inflammationagents) 2. In vivo, on rats 1. IN VITRO STUDY The activity of thecompound according to the invention in inhibiting contraction of theisolated guinea pig ileum provoked by biological inflammation agents isevaluated by its ED 50 (the dose required to give an inhibition of 50percent of the effect under consideration).

INFLAMMATORY AGENT lNHlBlTlNG AGENT Type Concentration EDSO of productEDSO of of the invention reference product Serotonine 5X10 g/l 1.7X10"gl Methylsergide 5,10 g/l Bradykinine 3.6Xl0 gl Naftidrofuryl: 4.1.10'g/l Histamine 2.4X10" gl Antazolin: 1.5,10" g/l vant arthritis).

Products Product Acetyl F lufenamic of the salicylic acid SOmg/kg Testsinvention acid (P.O.)

Carraghenin oedemas 200 166 200 planimetric value) (lll) Granulomata oncotton wool pellets of inhibition) l 7% inactive 20% FREUND Adjuvantarthritis (1) 30% 0% 50% age inhibition on the 21st day) (ll) 50% 50% l.Inhibition of primary arthritis (estimated by measuring the volume of apaw which has been subjected to injection).

ll. inhibition of secondary arthritis (estimated by measuring the volumeof a paw contra-lateral to that measured in l.

111. Planimetric value=sum of the percentage inhibition calculated everyhour for 7 hours.

Conclusion It is clear from the above tests that the product accordingto the invention is, in general, greatly superior dose mg/kg) to toacetyl-salicylic acid and equivalent to flufenamic acid (slightlyinferior in the granulomata and primary arthritis tests, but greatlysuperior in the secondary arthritis test): i

ll Anti-ulcerous activity This was investigated on several types ofexperimental ulceration in rats, namely l. central-origin ulcers(restraint ulcers), and 2. peripheral-origin ulcers (phenylbutazone,ligature of the pylorus, reserpine). l. LOCAL-ORIGIN ULCERS The productsare administered in a dose of 50 mg/kg P.O. (except for Atropine whichis administered in a batches of 10 rats; the study lasts for l8 hours.

The techniques used for creating gastric ulcers are conventional, namelya. ligature of the pylorus according to theSHAY technique. 7 I b. oraladministration of phenylbutazone in doze of 200 mg/kg. c. sub-cutaneousinjection of reserpinein a doze of 5 mg/kg. Results The following tableindicates the average values obtained with different products, thesevalues having been established in accordance with a scale which takesinto consideration the extent and gravity of the lesions. 1

Technique Ligature of Reserpine Phenylthe pylorus I butazone ProductProduct of the invention l0 6.4 22.3 Sulpiride 22 24.4 40.2 Atropine 8l0 l8 Controls- I untreated 27 2 l ,4 41,6

In all the tests as a whole, therefore, the product of the inventionshows a protective activity in respect of localorigin ulcers. Thisactivity is greatly superior to that of sulpiride and slightly inferiorto that of atropine.

2. CENTRAL-ORIGIN ULCERS Technique: Restraint of WlSTAR rats (180g)according to the BONFILS method.

Period of restraint: 24 hours Batch of animals Conclusion The productaccording to the invention has a very original effect on the ulcerationcaused by psychic stress. It is the only product to clearly amelioratethe congestive aspect and the vascularization of the mucous membrane.

As a result, the compound of the present invention appears to beespecially suited for the treatment of all attacks on the digestivemucous membrane, such as gastric ulcers, duodenal ulcers, gastritis,duodenitis, jejunitis, ileitis, rectitis, colitis, cholecystitis, etc.To this end, the product according to the invention can be administered:g

parenterally at a dosage of 10 to 50 mg/day orally at a dosage of to 200mg/day rectally at a dosage of to 300 mg/day 7 Thus the product of theinvention may be formulated as a solution for injection in sterilewater; as a syrup, linctus tablet or dragee for oral administration, oras a suppository for rectal administration.

The following examples of pharmaceutical composites in accordance withthe invention are given by way of illustration only.

Example 1 Injectable ampoules Product according to the invention 25 mgSodium chloride l2,8 mg Distilled water ad 2 ml Dissolve the product ofthe invention and the sodium chloride in the distilled water. Filter.Divide into 2 ml ampoules. Sterilize for 30 minutes at 1 10C.

Example 2 Syrup Formula for 100 ml Product of the invention 200 mg Sugar8] g Methyl parahydroxybenzoate 0,5 g Aromatics 5 ml Colorant 2 mgDrinking water ad lOO ml Product of the invention 87,5 mg Absolute ethylalcohol 1 ml Freon l2 6 ml Dissolve the product according to theinvention in the absolute ethyl alcohol before introducing the Freon 12.Example 4 Compressed as dragees a. Core Product of the invention 50 mgDicalcium phosphate 60 mg Colloidal silica 50 mg Corn starch 30 mg 4 mgPolyvidone magnesium stearate 4 mg Talc 2 mg Total: 200 mg Mix thepowders (except the talc) the magnesium stearate and one-third of thestarch.

Steep this mixture with ethyl alcohol at 30.

Granulate on a No. 30 AFNOR grid.

Dry this granulate for 30 minutes at 40 in air bed.

Add the talc, the magnesium stearate and one-third of.

the starch.

Compress to give 200 mg cores. b. Coating Gelatin Titanium oxide SugarWater Introduce the cores into a sugar-coating centrifuge. Pulverizethis syrup onto the cores in successive layers with intermediate hot-airdrying until a 350 mg dragee is obtained.

Example 5 Suppositories Product of the invention 100 mg Semi-syntheticglycerides 1900 mg Total: 2000 mg Introduce the product into theexcipient which has been melted beforehand.

Homogenize Pour into 2g moulds.

We claim:

1. For anti-ulcerous and anti-inflammatory treatment, a methodcomprising administering a medicament to a patient requiring suchtreatment, said medicament being administered in a pharmaceuticallyeffective dose and consisting of N-[2-phenyl-2-isoamyloxy]-ethyl-pyrrolidine.

2. A method as claimed in claim 1 wherein the medicament is administeredparenterally at a rate of 10 to 50 mg/day.

3. A method as claimed in claim 1 wherein the medicament is administeredorally at a rate of to 220 mg/day.

4. A method as claimed in claim 1 wherein the medicament is administeredrectally at a rate of to 300 mg/day.

2. A method as claimed in claim 1 wherein the medicament is administeredparenterally at a rate of 10 to 50 mg/day.
 3. A method as claimed inclaim 1 wherein the medicament is administered orally at a rate of 110to 220 mg/day.
 4. A method as claimed in claim 1 wherein the medicamentis administered rectally at a rate of 150 to 300 mg/day.